The present invention is related to a new use of sulfasalazine, and in particular, is related to a method for preventing neuronal death in brain diseases by administering sulfasalazine.
 less than Excitotoxicity and Brain Diseases greater than 
Excess activation of ionotropic glutamate receptors sensitive to N-methyl-D-asparte (NMDA receptors) produces neuronal death and has been known to mediate various neurological diseases [Choi, Neuron 1:623-634 (1988)]. Glutamate, an excitatory neurotransmitter, is massively accumulated in brain subjected to hypoxic-ischemic injuries, which activates ionotropic glutamate receptors permeable to Ca2xe2x88x92 and Na+ and then causes neuronal death [Choi and Rothman. Annu Rev Neurosci 13:171-182 (1990)]. Antogonists of NMDA receptors remarkably attenuate brain injury following hypoclycemia, hypoxia, or hypoxic-ischemia [Simon, Swan, Griffiths, and Meldrum. Science 226:850-852 (1984); Park, Nehls, Graham, Teasdale, and McCulloch, Ann Neurol 24:543-551 (1988); Wieloch, Science 230:681-683 (1985); Kass, Chambers, and Cottrell, Exp. Neurol, 103:116-122 (1989); Weiss, Goldberg, and Choi, Brain Res. 380:186-190 (1986)]. Thus, NMDA receptor antagonists possess therapeutic potentials to protect brain against hypoglycemia, hypoxia, and hypoxic-schemic injuries.
Excitotxicity appears to contribute to neuronal degeneration following traumatic brain injury (TBI). Levels of quinolinic acid, an endogenouis agonist of NMDA receptors, are increased 5- to 50-fold in human patients with TBI [E. H. Sinz, P. M. Kochanek, M. P. Heyes, S. R. Wisniewski, M. J. Bell, R. S. Clark, S. T. DeKosky, A. R. Blight, and D. W. Marion]. Quinolinic acid is increased in the cerebrospinal fluid and associated with mortality after TBI in humans [J. Cereb. Blood Flow Metub. 18:610-615, (1998)]. In animal models of brain trauma, levels of glutamate and aspartate were markedly increased. Faden, Demediuk, Panter, and Vink [Science 244:798-800 (1989)]. Glutamate release was also observed in rat spinal cord following impact trauma [Demediuk, Daly, and Faden. J Neurochem J. Neurochem. 52:1529-1536 (1989)]. NMDA receptor antagonists attenuate neuronal death following traumatic brain or spinal cord injuries [Faden, Lemke, Simon, and Noble. J. Neurotrauma. 5:33-45(1988); Okiyama, Smith, White, Richter, and McIntosh. J. Neurotrauma. 14:211-222 (1997)].
Glutamate plays a central role in the induction and the propagation of seizures. Dingledine, McBain and McNamara [Trends. Pharamacol. Sci. 11:334-338 (1990); Holmes. Cleve. Clin. J. Med. 62:240-247(1995)]. NMDA receptor antagonists were shown to act as anticonvulsants and antiepileptogenic drugs in various models of epilepsy [Anderson, Swartzwelder, and Wilson, J. Neurophysiol. 57:1-21 (1987); Wong, Coulter, Choi, and Prince. Neurosci. Lett. 85:261-266 (1988); McNamara, Russel, Rigsbee, and Bonhaus, Neuropharmacology 27:563-568 (1988)].
Amyotrophic lateral sclerosis (ALS) is accompanied by degeneration of both upper and lower motor neurons and marked neurogenic atrophy, weakness, and fasciculation. While the pathogenesis of ALS remains to be resolved, excitotoxicity has been expected to participate in the process of ALS. In particular, ALS patients show increased levels of extracellular glutamate and defects in glutamate transport. Administration of excitotoxins mimicked pathological changes in the spinal cord of ALS patients [Rothstein. Clin. Neurosci. 3:348-359 (1995); [konomidou, Qin, Labruyere, and Olney J. Neuropahol. Exp. Neurol. 55:211-224 (1996)].
Antagonizing NMDA receptors appears to be applied to treat Parkinson""s disease (PD). Several antagonists of NMDA receptors protect dopaminergie neurons from the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [Lange, Losehmann, Sofie, Burg, Horowski, Kalveram, Wachel, and Riederer, Naunym Schmiedebergs Arch. Pharmacol. 348:586-592 (1993); Brouillet and Beal. Neuroreport. 4:387-390 (1993)]. NMDA receptor antagonists also ameliorate levodopa-induced dyskinesia and thus can improve the therapeutic effects of levodopa [Papa and Chase. Ann. Neurol. 39:574-578 (1996) Marin, Papa, Engber, Bonastre, Tolosa, and Chase. Brain Res. 736:202-205 (1996)]. Two NMDA receptor antagonists, memantine and dextromethophan, have been proved beneficial in treating PD patients [Verhagen, Del Dotto, Natte, vand den Munekhof, and Chase, Neurology 51:203-206 (1998); Merello Nouzeilles, Cammarota, and Leiguarda, Clin. Neuropharmacol. 22:273-276 (1999)].
Huntington""s disease (HD) is a progressive neurodegenerative disease predominantly affecting small- and medium-sized interneurons but sparing NADPH-diaphorase neurons containing somatostatin and neuropeptide in the striata. These pathological features of HD are observed in the striatal tissues following the intrastriatal injections of quinolinic acid or cultured striatal neurons exposed to NMDA, raising the possibility that NMDA receptor-mediated neurotoxicity contributes to selective neuronal death in HD [Koh, Peters, and Choi, Science 234:73-76 (1986)]. Beal, Kowall, Ellison, Mazurek, Swartz, and Martin, Nature 321:168-171 (1986); Beal, Ferrante, Swartz, and Kowall, J. Neurosci. 11:1649-1659 (1991)].
 less than Free Radicals and Brain Diseases greater than 
Free radicals are produced in degenerating brain areas following hypoxic-ischemia or traumatic brain and spinal cord injuries [Hall and Braughler, Free Rudic. Biol. Med. 6:303-313 (1989); Anderson and Hall, Ann. Emerg. Med. 22:987-992 (1993); Siesjo and Siesjo, Eru. J. Anaesthesiol. 13:247-268(1996); Love, Brain Pathol 9:119-131 (1999)]. Antioxidants or maneuvers scavenging free radicals attenuate brain damages by hypoxic-ischemia or traumatic injuries [Faden, Pharmacol. Toxicol. 78:12-17 (1996); Zeidman, Ling, Ducker, and Ellenbogen, J. Spinal. Disord. 9:367-380 (1996); Chan, Stroke 27:1124-1129 (1996); Hall, Neurosurg. Clin, N. Am. 8:195-206 (1997)]. Extensive evidence supports that free radials can be produced in brain areas undergoing degeneration in neurodegenerative diseases possibly due to point mutations in Cu/Zn superoxide dismutase in ALS, decreased glutathione level and increased iron level in PD, accumulation of iron in AD, or mitochondrial dysfunction in HD [Rosen, Siddique, Patterson, Figlewicz, Sapp, Hentati, Donaldson, Goto, O""Regan, and Deng, Nature 362:59-62 (1993); Jenner and Olanow, Neurology 47:S161-S170 (1996); Smith, Harris, Sayre, and Perry, Proc. Natl. Acad. Sci. U.S.A. 94:9866-9868 (1997); Browne, Ferrante, and Beal, Brain Pathol. 9:147-163 (1999)]. Accordingly, antioxidants have been neuroprotective against such neurodegenerative diseases. Jenner, Pathol. Biol. (Paris.) 44:57-64 (1996); Beal, Ann. Neurol. 38:357-366 (1995); Prasad, Cole, and Kumar, J. Am. Cott. Nutr. 18:413-423 (1999); Eisen and Weber, Drugs Aging 14:173-196 (1999); Grundman, Am. J. Clin. Nutr. 71:630S-636S (2000)].
 less than Zine and Brain Diseases greater than 
Zn2+ mediates neurodegenerative process observed in seizure, ischemia, trauma, and Alzheimers diseases (AD). The central administration of kainate, a seizure-inducing excitotoxin, causes the translocation of Zn2+ into postsynaptic degenerating neurons in several forebrain areas [Frederickson, Hernandez, and McGinty. Brain Res. 480:317-321 (1989)]. Blockade of Zn2+ translocation with Ca-EDTA attenuates neuronal loss following a transient forebrain ischemia or traumatic brain injury [Koh, Suh, Gwag, He, Hsu, and Choi, Science 272: 1013-1016 (1996); Suh, Chen, Motamedi, Bell, Listiak, Pons, Danscher, and Frederickson, Brain Res. 852:268-273 (2000)]. Zn2xe2x88x92 is observed in the extracellular plaque and degenerating neurons in AD, which likely contributes to neuronal degeneration in AD [Bush, Pettingell, Multhaup, Paradis, Vonsattel, Gusella, Beyreuther, Masters, and Tanzi, Science 265:1464-1467 (1994); Suh, Jensen, Jensen, Silva, Kesslak, Danscher, and Frederickson, Brain Res. 852:274-278 852 (2000)].
The present invention provides a method for preventing neuronal loss in stroke, trauma, epilepsy and neurodegenerative diseases.
The present invention provides a method for protecting central neurons from acute or chronic injuries to central nervous system(CNS), which comprises administering appropriate quantity and forms of sulfasalazine to a patient or a mammal suffering CNS injuries.
The present invention still provides a method for reducing neuronal death in CNS injuries by administering appropriate quantity and forms of sulfasalazine that prevents NMDA-, Zn2+-, and free radical-mediated neurotoxicity simultaneously, said CNS injuries including ischemia, hypoxia, hypoglycemia, traumatic brain injury, traumatic spinal cord injury, epilepsy, Huntington""s disease, Parkinson""s disease, Alzheimer""s disease, or Amyotrophic lateral sclerosis.